Cystic fibrosis (CF) is an inherited condition that affects various parts of the body, particularly the lungs and digestive system. CF is the most common inherited disease in white people, affecting about 1 in every 2,500 children born. About one in five babies with CF are diagnosed at birth, when their gut becomes blocked by extra thick meconium. This condition may need surgery. Just over half of people with CF are diagnosed as babies because they are not growing or putting on weight as they should. This is because the pancreas is not producing sufficient lipolytic enzymes resulting in suboptimal assimilation of fat in food resulting in reduced caloric uptake and growth retardation. Untreated CF patients continue to have oily bowel movements, abdominal pain, and problems putting on weight. Constipation is also a frequent symptom. Occasionally the gut becomes completely blocked, resulting in extreme stomach pain.
CF is also characterized by lung involvement. In a healthy person, there is a constant flow of mucus over the surfaces of the air passages in the lungs which removes debris and bacteria. In CF, the mucus is excessively sticky and provides an ideal environment for bacterial growth. Patients with CF are at risk of bacterial chest infections and pneumonia. If they are not treated early and properly, these are very difficult to cure. Symptoms include persistent coughing, excess production of sputum (saliva and mucus), wheezing, and shortness of breath with ordinary activities. Other problems associated with CF have been identified.
CF is recessively inherited, the affected (CFTR) gene is located on chromosome number 7. The gene encodes the chloride channel CFTR. In cystic fibrosis (CF), the most common mutation delF508 which results in reduced activity and cell surface expression of the CF gene protein, the chloride channel CFTR. About 1 in 22 of the white population in the UK carry the delF508 CF mutation on one of the pair of number 7 chromosomes (“carriers”).
Presently no effective treatment for CFTR exists and therapy is restricted to combating symptoms. Patients with CF need daily chest physiotherapy, which involves vigorous massage to help loosen the sticky mucus. Patients also need to have any chest infection treated quickly with antibiotics. The usual childhood vaccinations, such as MMR (measles, mumps and rubella) and DTP (diptheria, tetanus and whooping cough) are important for people with CF, and they should also be vaccinated against flu and pneumococcus to help prevent chest infections. With each meal or snack, most people with CF need to take capsules that supply the missing pancreatic enzymes and allow proper digestion. Additional therapy may include daily oral or inhaled antibiotics to counter lung infection, inhaled anti-asthma therapy, corticosteroid tablets, dietary vitamin supplements, especially A and D, inhalation of medication (pulmozyme) to make the sputum less sticky, medicines to relieve constipation or to improve the activity of the enzyme supplements, insulin for CF-related diabetes, medication for CF-associated liver disease, oxygen to help with breathing and help to overcome fertility problems.
The most common CF mutation delF508 results in a mutant protein that is less efficiently folded in the ER, shows a reduced cell surface expression and reduced chloride current capacity. Several therapeutic approaches are considered for CF. One approach is based on gene therapy (introduction of correct CFTR cDNA). Alternatively, boosting of the activity of endogenous mutant CFTR is considered as therapeutic avenue. It is generally considered that a modest increase in chloride conductance of delF508 CFTR would be therapeutic. Investigated are therefore pharmacological improvements of mutant CFTR protein folding in the ER, pharmacological enhancement of cell surface expression of mutant CFTR protein and pharmacological potentiation of chloride conductance by the mutant CFTR protein. Presently, none of these approaches has resulted in an effective drug that corrects the primary problem in CF patients.
Correction of CF will require a correction of the underlying defect, i.e. correction of reduced activity of the chloride channel CFTR in apical membranes of epithelial cells. The majority of CF patients carries a mutant del F508-CFTR protein. The problem to be solved is therefore particularly to increase chloride currents in epithelial cells of patients carrying del F508-CFTR. For efficient therapeutic correction only a partial improvement chloride conductance capacity in these individuals is thought to be sufficient.